UOC Bioterapie, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy.
Università di Pavia "L. Spallanzani", Dipartimento Biologia e Biotecnologie, Lab. Anatomia Comparata e Citologia, Via Ferrata 9, 27100, Pavia, Italy.
Pharmacol Res. 2021 Jan;163:105294. doi: 10.1016/j.phrs.2020.105294. Epub 2020 Nov 17.
Caelyx and Myocet are clinically used liposomal forms of doxorubicin (Dox). To explore ways to improve their therapeutic index, we have studied their activity in vitro and in vivo when locally delivered by fibrin gels (FBGs). In vivo local toxic and anti-tumour activities of loaded FBGs were assessed in two immunodeficient mouse orthotopic human neuroblastoma (NB) models after application in the visceral space above the adrenal gland, either still tumour-bearing or after tumour removal. In parallel, in vitro assays were used to mimic the in vivo overlaying of FBGs on the tumour surface. FBGs were prepared with different concentrations of fibrinogen (FG) and clotted in the presence of Ca and thrombin. The in vitro assays showed that FBGs loaded with Myocet possess a cytotoxic activity against NB cell lines generally greater than those loaded with free Dox or Caelyx. In vivo FBGs loaded with Myocet showed lower general and local toxicities as compared to gels loaded with Caelyx or free Dox, and also to free Dox administered i.v. (all treatments with Dox at 2.5 mg/Kg). The anti-tumour activity, evaluated in the two mouse orthotopic NB models of adjuvant and neo-adjuvant therapy, resulted in a better performance of FBGs loaded with Myocet compared to the other local (FBGs loaded with Caelyx or free Dox) or systemic (free Dox) treatments (administered at 2.5 and 5 mg/Kg Dox). Specifically, the application of FBGs at 40 mg/mL in the adjuvant model caused 92 % tumour volume reduction, while by the neo-adjuvant application of FBGs at 22 mg/mL a re-growing tumour volume reduction of 89 % was obtained. Taken together, our in vitro and in vivo results indicate a significantly higher activity for the FBGs loaded with Myocet. In particular, the lower toicity coupled with the higher anti-tumour activity on both the local treatment modalities strongly suggest a better therapeutic index when Myocet is administered through FBGs. Therefore, FBGs loaded with Myocet may be considered as a possible new tool for the loco-regional treatment of NB or even other tumour histotypes treatable by loco-regional chemotherapy.
卡利霉素（Dox）和米托蒽醌脂质体（Myocet）是临床上应用的两种脂质体形式的多柔比星。为了探索提高其治疗指数的方法，我们研究了纤维蛋白凝胶（FBG）局部给药时它们在体外和体内的活性。在两种免疫缺陷型小鼠原位人神经母细胞瘤（NB）模型中，我们在肾上腺上方的内脏空间应用载药 FBG 后，评估了载药 FBG 的局部毒性和抗肿瘤活性，包括仍有肿瘤和肿瘤切除后两种情况。同时，我们还进行了体外实验以模拟 FBG 在肿瘤表面的覆盖。使用不同浓度的纤维蛋白原（FG）制备 FBG，并在 Ca 和凝血酶存在的情况下凝固。体外实验表明，载有米托蒽醌的 FBG 对 NB 细胞系的细胞毒性一般大于载游离多柔比星或卡利霉素的 FBG。与载有卡利霉素或游离多柔比星的 FBG 相比，载有米托蒽醌的 FBG 在体内具有更低的全身和局部毒性，也低于静脉注射游离多柔比星（所有多柔比星剂量为 2.5mg/kg）。在两种辅助和新辅助治疗的原位 NB 小鼠模型中评估抗肿瘤活性，结果表明，与其他局部（载有卡利霉素或游离多柔比星的 FBG）或全身（游离多柔比星）治疗（剂量为 2.5 和 5mg/kg 多柔比星）相比，载有米托蒽醌的 FBG 表现出更好的疗效。具体而言，在辅助模型中应用 40mg/ml 的 FBG 导致 92%的肿瘤体积减少，而在新辅助模型中应用 22mg/ml 的 FBG 导致 89%的复发性肿瘤体积减少。综上所述，我们的体外和体内结果表明，载有米托蒽醌的 FBG 具有更高的活性。特别是，较低的毒性与局部治疗方式更高的抗肿瘤活性相结合，强烈提示米托蒽醌通过 FBG 给药时具有更好的治疗指数。因此，载有米托蒽醌的 FBG 可被视为局部治疗 NB 或甚至其他可通过局部化疗治疗的肿瘤组织类型的一种新的潜在工具。
